New effective therapeutic approaches are needed for NSCLC. Antiangiogenic agents have recently emerged as a class of promising drugs. We hypothesize that simultaneously targeting both the tumor and its vascular supply using combinations of conventional chemotherapy and antiangiogenic agents will be more effective than either approach alone. Previously, we and others have demonstrated that conventional chemotherapeutic agents can act synergistically with angiogenesis inhibitors and may themselves have antiangiogenic activity--even against drug-resistant tumors--when administered on low dose, frequent schedules (metronomic dosing). The optimal means for combining chemotherapeutic agents and antiangiogenic therapy is not yet known. Studies have thus far been hampered by a lack of validated surrogate markers and appropriate animal models to test combinations before moving to human trials. In this project, we propose to investigate the combination of cytotoxic agents with angiogenesis inhibitors in both animal models and in patients with lung cancer. In the first aim, we will systematically assess combinations of taxanes and VEGFR inhibitors using murine models of NSCLC, and determine whether metronomic taxane dosing is more effective than conventional taxane dosing against sensitive and drug-resistant tumors. In the second aim, we will investigate the use of VEGFR inhibitors for different stages of lung cancer progression using a newly developed transgenic murine model. In the third aim, we will investigate the use of circulating endothelial cells and other potential surrogate markers for antiangiogenic activity and VEGFR inhibition. Finally, in the fourth aim, we will test a combination of ZD6474, a VEGFR antagonist, with docetaxel in a Phase II study of patients with NSCLC. In subsequent years, information from these clinical and preclinical studies will be integrated to create and test new combinations in future human trials. We believe that this coordinated, multifaceted approach moving between murine models and human trials will provide a more rational basis for the use of angiogenesis inhibitors in combination with chemotherapeutics for NSCLC and other cancers.